HER2 Positive Breast Cancer

P2, N=101, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Dec 2027 --> Jun 2028 | Trial primary completion date: Dec 2026 --> Jun 2027

P2, N=92, Completed, University of Nebraska | Active, not recruiting --> Completed | Trial completion date: Jun 2026 --> Nov 2025

Men with early-stage breast cancer exhibit lower responsiveness to neoadjuvant therapy than women, particularly in human epidermal growth factor receptor 2-positive (HER2+) disease. However, survival equivalence among responders underscores the continued value of neoadjuvant therapy in MBC.

This study identifies meaningful regional disparities in NAT receipt for TNBC and HER2+ breast cancer in Nova Scotia. Targeted strategies to improve guideline concordance are warranted and may lead to better patient outcomes.

These effects may be associated, at least in part, with alterations in Wnt/β-catenin signaling-related proteins and EMT-related markers. POC1A may represent a candidate molecular marker and potential target for further investigation in breast cancer, although its diagnostic, prognostic, and mechanistic significance requires further validation.

Completed trials with positive outcomes highlight PD-1-based and HER2-targeted bsAbs as the most promising candidates. These findings provide a data-driven roadmap for bsAbs development in breast cancer, emphasizing the need to optimize target combinations and identify predictive biomarkers.

The authors conclude that ecDNA amplification serves as a credible adverse prognostic indicator and holds promise for refining risk stratification and guiding treatment strategies. However, they stress that clinical adoption remains constrained by the absence of standardized, scalable, and reproducible detection.

Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) had BRCA2, and three (2.5%) had dual mutations; 66.9% received first-line therapy, with ribociclib in 69.4% and palbociclib in 29.8%. In multivariable analysis, ECOG ≥ 1 (HR 1.85; p = 0.010) and fulvestrant-based therapy (HR 1.74; p = 0.041) predicted shorter PFS; fulvestrant also predicted worse OS (HR 2.39; p = 0.008). CDK4/6 inhibitor-based therapy shows meaningful activity in gBRCAm HR+/HER2- MBC; the numerically poorer outcomes observed in BRCA2 carriers are hypothesis-generating and warrant validation in larger cohorts.

Ponatinib emerged as the top-ranked computational candidate (mean: - 10.07 kcal/mol), followed by Regorafenib (- 9.64), Sorafenib (- 9.46), and Entrectinib (- 9.45), while non-oncology drugs including antrafenine, betrixaban, and maraviroc demonstrated novel multi-target binding profiles...MM-GBSA calculations revealed a binding hierarchy concordant with docking scores (R2 = 0.92): Ponatinib-VEGFR2 (ΔGbind = - 42.38 kcal/mol) > Entrectinib-CDK6 (- 38.56) > Ponatinib-EGFR (- 33.24) > Entrectinib-HER2 (- 28.47) > Dacomitinib-HDAC3 (- 24.63 kcal/mol)...As the present study is entirely computational, the identified compounds should be regarded as hypothesis generating leads requiring experimental validation through in vitro kinase and HDAC3 inhibition assays, cell based studies, and target engagement confirmation before any translational conclusions can be drawn. The online version contains supplementary material available at 10.1007/s40203-026-00681-w.

Therefore, in collaboration with a research group at Dalian University of Technology, we synthesized ZQL-4c, a novel oleanolic acid (OA) derivative that was found to target the lipid metabolism reprogramming function of stearoyl-CoA desaturase (SCD), inducing lipotoxicity-mediated apoptosis. These findings provide an attractive future direction for the treatment of HER2-positive trastuzumab-resistant breast cancer.

Circulating tumor DNA mutation status may serve as a prognostic biomarker in patients receiving HER2-targeted therapies. PIK3CA mutations were associated with worse outcomes, whereas ERBB2 mutations showed no significant effect. The prognostic significance of ctDNA was most pronounced in patients treated with TKIs, particularly pyrotinib, and remained evident in monotherapy and capecitabine-based regimens. These findings support the potential utility of ctDNA monitoring for risk stratification and personalized management in advanced HER2-positive breast cancer.

Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting. ClinicalTrials.gov Identifier: NCT03716180.